Synthesis and anti-Mycobacterium tuberculosis activity of imide-ß-carboline and carbomethoxy-ß-carboline derivatives.

A series of methyl ß-carboline carboxylates (2a-g) and of imide-ß-carboline derivatives containing the phthalimide (4a-g), maleimide (5b, g) and succinimide (6b, e, g) moiety were synthesized, and evaluated for their activity against Mycobacterium tuberculosis H37Rv. The most active ß-carboline derivatives against the reference strain were assayed for their cytotoxicity and the activity against resistant M. tuberculosis clinical isolates. Farther, structure-activity relationship (SAR) studies were carried out using the three and four-dimensional approaches for starting to understand the way of ß-carboline activity in M. tuberculosis. All 19 ß-carboline derivatives were assayed, firstly, by determining the minimum inhibitory concentration (MIC) using resazurin microtiter assay plate (REMA) in M. tuberculosis H37Rv. Then, five derivatives (2c, 4a, 4e, 4g, 6g), which showed MIC ≤ 125 µg/mL, were assayed in nine resistant M. tuberculosis clinical isolates (five MDR, three isoniazid monoresistant and one isoniazid plus streptomycin resistant). The MIC values against the resistant clinical isolates ranged from 31.25 to >250 µg/mL. All five derivatives were non-cytotoxic to the VERO cell line, determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, at the tested concentration (selectivity index ranged from <1.74 to 14.4). Our study demonstrated that (2c) and (6g) derivatives had better anti-M. tuberculosis activity, especially against resistant clinical isolates, what makes them scaffold candidates for further investigations about their anti-tuberculosis activity. The SAR study conducted with the 19 ß-carboline derivatives showed the importance of steric effects for the synthesized ß-carbolines against M tuberculosis, and these models can be used for future proposition of new derivatives, increasing the chances of obtaining potentially anti-tuberculosis compounds.

In silico study toward the identification of new and safe potential inhibitors of photosynthetic electron transport.

To address the rising global demand for food, it is necessary to search for new herbicides that can control resistant weeds. We performed a 2D-quantitative structure-activity relationship (QSAR) study to predict compounds with photosynthesis-inhibitory activity. A data set of 44 compounds (quinolines and naphthalenes), which are described as photosynthetic electron transport (PET) inhibitors, was used. The obtained model was approved in internal and external validation tests. 2D Similarity-based virtual screening was performed and 64 compounds were selected from the ZINC database. By using the VEGA QSAR software, 48 compounds were shown to have potential toxic effects (mutagenicity and carcinogenicity). Therefore, the model was also tested using a set of 16 molecules obtained by a similarity search of the ZINC database. Six compounds showed good predicted inhibition of PET. The obtained model shows potential utility in the design of new PET inhibitors, and the hit compounds found by virtual screening are novel bicyclic scaffolds of this class.

Multivariate QSAR study on the antimutagenic activity of flavonoids against 3-NFA on Salmonella typhimurium TA98.

A quantitative structure-activity relationship (QSAR) study of twenty flavonoid derivatives with antimutagenic activity against 3-nitrofluoranthene (3-NFA) was performed by Partial Least Squares (PLS), using Ordered Predictors Selection (OPS) algorithm for variable selection. Four descriptors (PJI2, Mor27m, G1e and R4u+) were selected and a good model (n = 19; R(2) = 0.747; SEC = 0.332; PRESS(cal) = 1.768; F((2,27)) = 23.585; Q(LOO)(2) = 0.590; SEV = 0.388; PRESS(val) = 2.858; R(pred)(2) = 0.591; SEP = 0.394; ARE(pred) = 5.230%; k = 1.005; k' = 0.990; |R(02) - R'(02)| = 0.109) was built with two latent variables describing 83.410% of the original information. Leave-N-out cross validation (LNO) and y-randomization were performed in order to confirm the robustness of the model. The topological descriptors selected indicate that the antimutagenic activity against 3-NFA depends on molecular size, shape and Sanderson electronegativity of flavonoids. The proposed model may provide a better understanding of the antimutagenic activity of flavonoids and can be used as a guidance for proposition of new chemopreventive agents.

[Description of attempts to obtain approval for selling medications at ordinary Brazilian establishments after the introduction of the Real Economic Stabilization Plan]. / Histórico das tentativas de liberação da venda de medicamentos em estabelecimentos leigos no Brasil a partir da implantação do Plano Real.

Although not legal, the practice of selling medications through unlicensed outlets such as stores and supermarkets has long been common in Brazil. Introducing the Real Economic Stabilization Plan, Provisional Measure 592/94 allowed the sale of non-prescription medications (anodynes) in such establishments. However, this item was suppressed when this Provisional Measure was enacted as Law N masculine 9,069/95. Since then, other attempts have been made to establish this type of trade in medications, forbidden in 2004 through a decision handed down by the Superior Court of Justice. Nevertheless, this unlawful trade in medications still continues. Due to the scarcity of publications on this specific issue, this paper offers an updated overview for druggists, pharmacists, academics and researchers, describing the events that took place between 1994 and 2006.